Aryl carboxylic acid esters and methods for obtaining the same



Patented May 29, 1945 aavassc ABYL CARBOXYLIC ACID ESTERS AND METHODS FOR QBTAINING THE SAME Frederick F.- Blicke, Ann Arbor, Mich., assignor to The Regents of the University of Michigan, Ann Arbor, Mich., a body corporate of Michigan No Drawing. Application July 12, 1941, Serial No. 402,244

' 7 Claims.

This invention relates to the preparation of new aminoalkyl esters of substituted phthalic acids and their acid addition salts, said compounds being useful anesthetics of surprisingly high potency. 1

The new esters'are representable by the following structural formula:

6 6 5 1 000R. (FUDGE; COOK: coca,

In all cases the compounds in which Y is --NH2 can readily be prepared from the corresponding compounds in-which Y is -NO2 by treatment of the latter type of compound with a reducing agent capable of reducing a --NO2 group toa group. Such reducing agentsand techniques 3.11%

clude the use of stannous chloride, iron powder in aqueous suspension, titanous chloride, catalytic hydrogenation in the'presence of a suitable catalyst such as platinum, palladium or nickel, and so forth.

The compounds in which Y is -NO: can be prepared from the nitrophthalic acids or the anhydrides thereof.

For example, 3 -nitrophthalic anhydride may be mono-esterified by treatment with an aliphatic I alcohol such as ethyl alcohol, amyl alcohol, ethylene glycol mono-ethyl ether, diethylaminoethyl alcohol, cetyl alcohol. N-morpholino-ethanol, etc. Thus, there is obtained a compound oi'the formula,

-ooon COO-R where R is an alkyl, alkoxyalkyl or substitutedamino-alkyl. This substance may then be further esterified with asecor tertamlnoalkanol, thereby forming a compound of the type,

, N0: where R' is an alkyl group substituted bya sec- ,or tertamino group.

The esteriiication in the last step above and in similar examples which will follow, m ay be accomplished by a variety of methods. For example, the acid may be converted into the corresponding acyl halide by treatment with thionyl chloride, phosphorus pentachloride, phosphorus tribromide and similar halogenating agents; the acyl halide thus produced is reacted with the aminoalkanol, thereby providing the desired ester. Alternatively, the acyl halide may be reacted with a haloalkanol, such as ethylene bromohydrin, and the resulting ester subsequently condensed with apri or secamine.

I have found that aminoalkanol esters of sub stituted phthalic acids are readily prepared by reacting the corresponding acid, e. g., the Z-morio ethyl ester otfi-nitro-phthalic acid, witha tertaminoallryi halide. This may be illustrated by the following equation:

+C1CH:CH2N(CSHE)H coo Unfit 2 mementos mam H or i G 0 0 02115 'NOQ) It is evident that this condensation yields the esters in the form of their hydrohalides. The ester bases are readily prepared from the hydrohalides by treatment with an alkaline reagent such as potassium hydroxide, sodium carbonate, and the like.

To prepare isomeric compounds of my inven-' tion, advantage is taken of the fact that 3-nitrophthalic anhydride reacts with alcohols to form monoesters isomeric with those obtained by direct monoesterification of 3-nitrophthalic acid with the alcohol. This may readily be seen by a comparison of the generalequations for the two types of reactions, a

A 0 00011 ROE i c COOR or. p-toluenesulfonic acid.

When 4-nitrophthalic acid or its anhydride are 1 following examples:

COOH

ROH

ooon' COO-R COOH ' Reaction A takes place simply on heating the alcohol, ROH, with the anhydride; but to effect reaction B, it is usually necessary to heat the acid with the alcohol in the presence of a strong acid:

catalyst such as sulfuric acid, hydrochloric acid,

used according to schemes B or A respectively,

using a simple unsubstituted alcohol such as ethyl alcohol or amyl alcohol, the same product is obtained in each case, namely, the l-mono-ester of d-nitrophthalic acid,

om coon However, the isomeric product,

I I -o on om coon is obtained by employin either method A or B on a substituted alcohol such as ethylene bromo- ,hydrin or diethylaminoethyl alcohol.

it will be evident in view of the foregoing discussion that by a suitable combination of the methods described above, anyof the isomeric compounds of my invention may readily be obtained.

The new compounds of-my invention, comprising both the basic esters and their acid addition aminoethyl p aminobenzoate) and are less toxic.

than cocaine. a

- For many purposes the new anesthetics are best employed in the form of their substantially nontoxic-acid addition salts. Such salts include the hydrochlorides, hydrobromides, sulfates, sulfamates, phophates, borates, acetates, citrates, tartrates, malates, lactates, and so on. The term substantially non-toxic acid used in this connection in this specification, and in the appended claims is to be understood to mean acids which are not toxic in the amounts administered in combination with the anesthetic.

e The salts described above are readily prepared by reaction of the ester base with the acid, prefer ably in a solvent in which both the base'and the acid are soluble.

It will be noted that in the case where Y is 'NH: the new anesthetic bases have at least two amino groups. Of these the amino group in the side chain or ester grouping is considerably more basic, so that commonly, onlythis 'group is involved in salt formation. 'However, the ring amino group may be involved insalt formation ii a considerable excess of acid is employed.

Mydnvention can be further illustrated by the as'rasco Example 1.-Preparation of i-ethyl z-m-aiem zam' inoethyl) 3-amino-phthalate A. l-ethyl 3-nitroacidphthaZata-A mixture of 105.5 of B-nitrophthalic acid (Culhan'e and Woodward, Organic Syntheses, collective volume I, John Wiley and Sons, Inc., New York, 1932, p. 399), 100 cc. of absolute alcohol and 10 cc. of concentrated sulfur'icacid is heated at 125 in an oilbath for nine hours.- The excess alcohol is removed by distillation under diminished pressure. the residue washed with cold water andtreated with 10% sodium carbonate solution. Thealkaline mixture is extracted several times with ether to remove diethyl 3-nitrophthalate and then acidified'with dilute hydrochloric acid. The solid monoethyl ester of 3-nitrophthalic acid which precipitates is filtered and recrystallized from benzene; M. P. 11-112 C.

B. l-ethyl Z-(p-diethylaminoathyl) 3 -mtrophthalate. -A solution of 11.9 of l-ethyl 3-nitroacid-phthalate and 6.5 of p-diethylaminoethyl chloride in 30 cc. of isopropyl alcohol (which previously has been treated with sodium and distilled) is refluxed on a steam-bath for twelve hours. The solvent is removed by distillation under diminished pressure and the residue washed With absolute ether. This residue is the hydrochloride of l-ethyl 2-(p-diethylaminoethyl) B-ni'trophthalate, and it may be purified by recrystallization from a mixture of ethyl acetate and absolute alcohol; M. P. 126-128 C.

Anal..: Calcd. for CmHzaOsNzCl: Cl, 9.46.

v Found: Cl, 9.64.

C. I-ethyl Z-(fl-diethylarftinoethyZ) 3-aminophthalate hydrobr0mide.- -To a solution of 8.8 of 1 ethyl 2 o-diethylamin'oethyl) 3 nitrophthalate in 10 cc. of acetic acid is added 16.5 of powdered stannous chloridedihydrate. The mix ture becomes hot suddenly and it is necessary to cool it rapidly. It is then saturated with hydrogen chloride, thev temperature being i naintained at 40-50% Any undissolved 'stannous chloride soon disappear's. After three to four hours the mixture is dissolved in 100 cc. of water and treated with a 10% solution of sodium hydroxide until the tin hydroxide has precipitated and redissolved. During this process the mixture must be cooled. The liberated oily base is extracted with ether and the ethereal solution dried with sodium sulfate. moved and the oily residue treated with 0.908

cc. of concentrated hydrobromic acid (48%).

After thirty minutes theoily hydrobromide of I-ethyl 2-"(B-diethylaminoethyl) 3-aminophthalate is' rubbed under anhydrous" ether, whereupon it solidifies immediately.- It is recrystallized from a mixture of ethyl acetate and absolute alcohol; M. P. 112-113? 0.

Anal.: Calcd. for C1eH25O4N-2Br: Found: 20.60. X i Example 2.-'-Preparation of I-iS MOMJZ Z-(p-diethylaminoethyl) 3-aminophthalate A; Z-(p-diethylaminoethyl) '3-mtroacidphthalate.To a solution of 59.7 g. of 3-nitrophthalic anhydride (Nicolet and Bender Organic Syn- The solvent is re-' Br, 20.52. L I I whereupon it becomes crystalline.

aavaaoo 1 Y 3 Ami;- Calcd. for CllHleOtNfl: N, 9.03. mm:

13. Acid chloride of ZKB-diethyiaminoethyl) 3- nitroaeidphthalateJ-A mixture of 15.5 gr'of 2- (p-diethylaminoethxl) 3-nitroacidphthalate and 30 cc. of thionyl chloride is refluxed on a steam bath for flve hours. The excess thionyl chloride is removed by distillationunder reduced pressure and the gummy residue washed in the reaction flask with absolute ether. The crude hydrochloride of the acid chloride of 2-(fl-diethylaminoethyl) 3-nitroacidphthalate is used in r the following preparation without further puriflcation.

C. l-isopropyl z-(e-diethylammoethyl) 3-mtrophthalate hydrobromide.-The acid chloride,

described above, is dissolved in 30 cc. of isopropyl alcohol, the solution is refluxed on a steam bath for three hours and the excess alcohol then removed by distillation under diminished pressure. The residue is cooled, dissolved in water, the solution made alkaline with sodium carbonate solution, extracted threetimes with ether,

and the combined ether extracts dried with so-.

"is treated with hydrogen. chloride in the manner described in Example 1C. In order to prepare 40 Anal:

the citrate. 7.15 g. of the oily diester base and 4.65 g. of citric acid monohydrate are heated in absolute alcoholic solution cc.) on a steam bath for about k hour. The solvent is evaporated and the residue washed with absolute ether, The citrate of l-isopropyl 2-(fi-die thylaminoethyl) 3-amino'- phthalate melts at 86-89 C.

Anal: Calcd. mfcamionmz 11,-5.44. mind: N, 5.51.

I Example 3.- -Preparation of I-(p-dlethulaminoethyl) z-n-promll 3-aminophthalate A. Z-DTOMIZ 3-nitr0acidphthalate.A solution of 48.5 g. of 3-nitrophthalic anh'ydrlde in '75 cc. of dry n-propyl alcohol is refluxed on a steam bath for live hours and the excess alcohol removed by distillation under reduced pressure.

The residue is cooled, treated with a 10 solution of sodium carbonate, the mixture filtered and the filtrate acidified with concd. hydro-' chlorlc acid. The precipitated mono-ester is col- 15 lected by filtration and recrystallized from dilute alcohol; M. P. 139-140 C.

B.1-(,3-diethylaminoethyl) Z-m-propyl 3-nitrophthalate hydrochloride-A mixture of 12.65

g. of 2-n-propyl 3-nitroacidphthalate, 6.6 g. of

20.,p-diethylaminoethyl chloride (Slotta'and Behnisch, Ber., 68, 758 (1935)) and cc. of dry isopropyl alcohol is refluxed on a steam bath for fivehours and the solvent removed'by distillation under reduced pressure. The crude hydro- 25 chloride ot'the diester is purified by recrystallization from ethyl acetate; M. P; 111-112 0.

Anal: Calcd. for CiwHasOeNaCl: Cl. 9.12. Found: Cl, 924.

' c. l-(p-diethylaminoethyl 2 n propyl 3- aminophthalate hydrochloride.The nitro' group in the diester is reduced in a manner analogous to that described in Example 16. The hydrochloride of l-(p-diethylaminoethyl) 2-n-propyl S-aminophthalate is prepared by treating the oily base with the calculated amount of concd. hydrochloric acid and purified by recrystallization from a mixture of ethyl acetate and absolute alcohol; M. P. 129-130" 0.

Found: Cl. 9.96. r v

My invention is not limited to the 3-aminoand 3-nitrophthalic acid esters described in the above examples. By using essentially the same procedures many similar ester types may be prepared; The following list gives some of the new compounds with their melting points:

Salts of esters of 3-nitrophthalicacid 6 1 370003, Vcooia R B: Formula M'CIT" o H200N2.HC1 139-140 ciZmoimnm... l26l28 CnHuOnNmHCl..- 93-95 Calcd. 1 for cnrnioimciz Cl. 9.88. p

' c n 0N.HBr 131-139 oliriiiozisloiahi -156 C aHn'O N CHQI 164-165 v 2 ,876,860 I Salts of esters of s amincphthalic acid It will be'noted that some of the esters have been characterized in the form of their duster-- nary salts, since a few of the simple hydrohalides are not readily obtained in crystalline form.

Formula ab CwHnOrNaHCl 114-115 1 2. CmHuOlNaHBr 112-113 3. CnHggChNg-HBI' 107-105 1 4 CnHzeO NQ-CsHBOKBRlMO)- 86-3 1 5- CxaHasQNi-HBI'. 91-93 1 6. C s HB 110-112 1 7 o sHzeo Ni.CsHaOfldltiBtG) 92-95 1 8 CmHsoOlNmCsHaOKdiil'BiB) 81-83 '9- d0 C2oHzOlNaCsHsO7c1tmtM 79-81 10. CHzC (CH!)2CH2N (CHa) C1aHIs04Nz-C5Hs07 citrate) 145-146 CH:CH:N(C2H;): -inO4N:.H 7 150-152 12. rln v CuHuOlNaHCL. 139-140 13. rln 1HzaO4Ni-H 129-130 g 14- on on) do i C 1H O4N .HCluse-154 I 15. CH: HzCHgCHz d0 C sHuO4NaIIC 117-118 116". CHICHGQHQ; Iin ssOlNa- 1 3-11 .17-.- CH(OH:)CH lBH2B04N2-HBL- 117-118 .18 CH: CHfiaCHs. r h oHmO4N1.HBr 90-92 19. CH: CHMCHa. r o 02cHno4NI-coH801 72-74 CHz(CHz)mCHa.- n CzsH4xO4N:-CsHs01-- 84-8 21... CHz(CH)mCH1 n szHs'uOcNz BSBL..- 45-46 2- CHsCHiCHa CHICHQCHNCIHIO (N-plperidino-n-propyl CmHzsOlNaHCL 1 3-124 3 CHiCHzCHa CH)CH:CH:N(C4HI)1 C:zHu04Na.HBr- 115-116 cflioHlcHnnc'. CH:C(CH:):CH:N(CH3): CIBHQBOJNI-HBI' 139-141 phthalate hydrochloride-Eire nitro group is Example 4.-Preparation of I-methyl -(B-di- I j ethylaminoethyl) 4-aminophthalate hydrol chloride 7 The 4-nitrophthalic anhydride used in the following preparation was obtained from -i-nitrophthalic acid (Huntress, Schloss and Ehrlich;

Organic Syntheses, vol.. 16, John Wiley 81' Sons, Inc., New York, 1936, p. 56) by the method of Qulhane and Woodward (10c. cit.) used for the preparation of the corresponding 3-nitro com- Pound.

j A. I-methyl 4-nitroacidphthalaie.A mixture of 57.9 g. of i-n'itrophthalic anhydride and 150' cc. of absolute methyl alcohol is refluxed on a steam bath for about ten hours. The excess sol vent is removed liyv distillation under reduced pressure. The cooled oily residue is washed well. with water; whereupon a white solid separates. It is dissolved in 1.0% sodium carbonate solution to remove any diester which might have been formed and any unchanged anhydride. The sodium carbonate solution is neutralized with concd. hydrochloric acid. An oil separates which solidifies after being chilled in an ice bath for several hours. The solid is filtered, washed well with water, andrecrystallized five times from hot water; M. P. 129-131 C. Y B. I-methyl z-(p-dicthulaminoethyl) .4-nitroflhtha late hydrochlorides -A solution of 2.25 g. of l-methyl 4-nitroacidphthaiate and 1.36 g.-oi

- diethylaminoethyl chloride in 30 cc. oi isopropyl alcohol is refluxed for about ten hours on a steam bath. The excess solvent is removed by dis-. vtillation under diminished pressure, and an oily residue obtained which solidifies after having been washed thoroughly with anhydrous ether; M. P. 164469 0.

;Anal.: Calcd. for CmHmCsNzCl! C1,- 9.84,

Found: Cl, 9.52.

reduced in a manner analogous to that described in Example 10. The hydrochloride of l-methyl 2 -(p-diethylaminoethyl) 4-aminophthalate is prepared by the addition of the calculated 1 amount of concd. hydrochloric acid to the oily base and purified by recrystallization from a mixture of ethyl acetate and alcohol; M. P. 166-168" C. I

AnaL: Calcd. for CrsI-ImOcNzCl: Ci, 10.74. Found: Ci, 10.81.

Example 5.Premration of l-ethzll z-id-di-woropylaminoethyl) d-aminophthclate hydrochloride C A. To a solution of 193 g. of -nitrophthalic anhydride in 200 cc. of dry benzene is added 131 g. of ethylene bromohydrin and the mixture is refluxed on a steam bath for one hour. The

. excess solvent is removed under reduced pressure. The residue and reddish oil is washed well with water and treated with a. 10% sodium carbonate solution. The alkaline solution is shaken with ether and then neutralized with concd; hydrochloric acid; during the lattervproeess, the mixture is cooled to prevent hydrolysis. The oil which separates becomes solid afterbelng chilled (for several. hours in an ice bath. The white solid is filtered, washed well with water. and dried; M. P. Bil-101 0.

AnaL:

' Found: Br, 25.07.

B. Acid chloride of z-bromoethyl d-nitroacid- .phthalate.--A mixture or 13 g: of z-bromoethyl Calcd. for Q1oHsOeNBr; at, 25.15.

in the subsequent pr p.

v is made alkaline with a 10% sodium'carbonate hol is added, and the mixture refluxed for about mixture of ethyl acetate and alcohol; M. P. two hours. The excess solvents are removed 114-1'16 C. v

under diminished pressure and the brownish Anal: Calcd. for C18H2904N2'C11 Cl, 9.53. residue washed with sodium carbonate solu- Found: 01, 9.66

tion, then with water, and finally taken up in 5 Other esters of 4-nitro-4-aminophthalic acid ether. The ether solution is dried with fused may be obtained by essentially the same procesodium sulfate and the solvent removed. The dures. For example, the following. compounds oliester is obtained in the form'of a. brownish .oil. have been made:

Salts of esters of d-nitrophthalic acid CHzOHzN Salts of esters of 4-aminophthalic acid RN 000m A v No. I R1 Ra Formula OH CH OHN CH 0 H 0N .HCl-. 166-168 015cm an 2 z 1 01211220512301 152-153 CHrCHzC C11H2QOAN:.HBI--.'-.. 117-118 CH(CH;): (in CnHgnO4Nz.CeHx01 citrate 97-99 omcmomom; on GlBHiSOiNi-CtHEO'I citrate 93-94 CHzCH(CHqh do C1aH:a04N:.CsHsO1(0ltrBte 102-104 CH(CHa)CHzCH- do 015%:304N2D5H50Hz1(benzylio- 79-83 e 8 011 CHQCH1N(C3H1)2 9. CH CBhNCsHm 1O... d0 CHzCHaNC HaO D. I-ethyl 2-(B-di-n-proplyaminoethyll 4-m'- Some, of the monoesters of 4-amin ophthalic mphthalate hydrochloride-A solution of 37.5 acid which have been used as intermediates are g.'of' l-ethyl 2-bromoethyl 4-nitrophthalate and new compounds. For example, the following 27.4 g. of di-n-proplyamine in cc. of dry havebeen made: toluene is refluxed in an'oil bath at 11o-115 C.

for four hours: h white crystalline Dre-mph I-monoalkyl esters of 4 mtrophthalic acid tate of di-n-propylamine hydrobromide is re- 6 moved by filtration and the filtrate concentrated. 5 1 The residue is washed-well with water and then ON 2 C003 dissolved in 5% hydrochloric acid. The solution a GOOB.

solution and the basic ester extracted with ether. The solution is dried with fused sodium sulfate.- and the solvent removed. To the weighed oily residue is added the calculated amount of 'a'. standardized alcoholic solution of hydrogen chloride. The excess of alcohol is removed and the residue washed with anhydrous ether. The white solid which separates is recrystallized from a mixture of etheracetateand alcohol; M. P.

Formula 143-144" 0. What I claim as my invention is:

Anal-.1 Calcd. for CmHmOcNzCl: Cl, 8.82.-- 1. A compound ofthe class an amino alkyl d: Cl, 8.96. Y ester of a nuclearly amino substituted phthalic E. I-ethyl z-di-n-propylamimoethyl 4-aminoacid and its substantially non-toxic acid addiphthalate hydrochloride.-,-'lhis compound is pretion salts characte i ed by the following formula pared from the corresponding nitro ester in the for the r, manner described in Example 1C. The hydrochloride is prepared by treating the oily base with I": the calculated amountvof concd. hydrochloric acid, and purified by recrystallization from a u tvh'ere R is an alhl radical containing not more than !7 carbon atoms and R1 is a member of the class consisting of dialkyl aminoalkyl, N-mo'r- Dholino alkyl and N-piperidino alkyl. 1 2. A compound oi..the class an amino alkyl ester of a nuclearly amino substituted phthalic acid and its substantially non-toxic acid addition salts characterized by thefiollowing formula or the ester,

HIN I.

where R is an'alkyl radical containingnot more than seven carbon atoms. J I

5 3. A compound of the class an amino alkyl ester of a nuclearly amino substituted phthalic acid and its substantially non-toxic acid addition CsHs c 0 o-cmr-N CzHs coo-R I where R is an alkyl radical containing not more than seven carbon atoms.

5. The class of compounds consisting of the free amino form and its substantially non-toxic- 'acid addition salt forms of an aminoalkyl ester 14. The'class of compounds consisting of the free amino form and its substantially non-toxicacid addition salt forms of an aminoalkyl ester of a phthalic acid of the formula,

1 I ClHs C 0 O-CaHlN CaHt COO-propyl 01' a phthalic a of the formula,

V can; 1 coo-mm-r/ CaHs COO-butyl 6. The class or compounds consisting of the free amino formiand its substantially non-toxicacid addition salt forms of an aminoalkyl ester 01' a phthalic acid of the formula,

7. The class of compounds consisting of the free amino form audits substantially non-toxici acid addition salt forms of an aminoalkyl ester of a phthalic acid 01' the formula,

\ s. 31.1mm 

